A T cell immune response is a complex process that involves cell-cell interactions (Springer et al. (1987) Ann. Rev. Immunol. 5:223-252), particularly between T and accessory cells such as APC's, and production of soluble immune mediators (cytokines or lymphokines) (Dinarello (1987) New Engl. J. Med. 317:940-945; Sallusto (1997) J. Exp. Med. 179:1109-1118). This response is regulated by several T-cell surface receptors, including the T-cell receptor complex (Weiss (1986) Ann. Rev. Immunol. 4:593-619) and other “accessory” surface molecules (Allison (1994) Curr. Opin. Immunol. 6:414-419; Springer (1987) supra). Many of these accessory molecules are naturally occurring cell surface cluster of differentiation (CD) antigens defined by the reactivity of monoclonal antibodies on the surface of cells (McMichael, Ed. (1987), Leukocyte Typing III, Oxford Univ. Press, Oxford, N.Y.).
CD28 antigen, a homodimeric glycoprotein of the immunoglobulin superfamily (Aruffo and Seed (1987) Proc. Natl. Acad. Sci. USA 84:8573-8577), is an accessory molecule found on most mature human T cells (Damle et al. (1983) J. Immunol. 131:2296-2300). Monoclonal antibodies (MAbs) reactive with CD28 antigen can augment T cell responses initiated by various polyclonal stimuli. Anti-CD28 mAbs can also have inhibitory effects, i.e., they can block autologous mixed lymphocyte reactions (Damle et al. (1981) Proc. Natl. Acad. Sci. USA 78:5096-6001) and activation of antigen-specific T cell clones (Lesslauer et al. (1986) Eur. J. Immunol. 16:1289-1296). CD28 is a counter-receptor for the B cell activation antigens B7-1 and B7-2.
CTLA-4 is a T cell surface molecule that was originally identified by differential screening of a murine cytolytic T cell cDNA library (Brunet et al. (1987) Nature 328:267-270). CTLA-4 is a member of the immunoglobulin (Ig) superfamily, comprising a single extracellular Ig domain. CTLA-4 transcripts have been found in T cell populations having cytotoxic activity (Brunet et al., supra; Brunet et al. (1988) Immunol. Rev. 103:21-36). Researchers have reported the cloning and mapping of the human CTLA4 gene (Dariavach et al. (1988) Eur. J. Immunol. 18:1901-1905) to the same chromosomal region (2q33-34) as CD28 (Lafage-Pochitaloff et al. (1990) Immunogenetics 31:198-201). Sequence comparison between this human CTLA-4 DNA and that encoding CD28 proteins reveals significant homology of sequence, with the greatest degree of homology in the juxtamembrane and cytoplasmic regions (Brunet et al., 1988, supra; Dariavach et al., 1988, supra).
It has been established that CTLA-4 acts as a negative regulator of T cell activity. For example, it has been reported that CTLA-4 deficient mice suffer from massive lymphoproliferation (Chambers et al. (1997) Immunity 7:885-895). It has also been reported that CTLA-4 blockade, using anti-CTLA-4 antibodies, augments T cell responses in vitro (Walunas et al. (1994) Immunity 1:405-413) and in vivo (Kearney (1995) J. Immunol. 155:1032-1036), exacerbates antitumor immunity (Leach (1996) Science 271:1734-1736), and enhances an induced autoimmune disease (Luhder (1998) J. Exp. Med. 187:427-432). It has also been reported that CTLA-4 has an alternative or additional impact on the initial character of the T cell immune response (Chambers (1997) Curr. Opin. Immunol. 9:396-404; Bluestone (1997) J. Immunol. 158:1989-1993; Thompson (1997) Immunity 7:445-450). This is consistent with the observation that some autoimmune patients have autoantibodies to CTLA-4. It is possible that CTLA-4 blocking antibodies have a pathogenic role in these patients (Matsui (1999) J. Immunol. 162:4328-4335). Given the ability of anti-CTLA-4 antibodies to stimulate immune responses, such antibodies are being pursued as therapeutic agents in the treatment of tumors, viral diseases and other clinical indications in which an enhanced immune response is desirable (see e.g., U.S. Pat. No. 5,811,097, No. 5,855,887 and No. 6,051,227, and PCT Publication WO 01/14424).
CTLA-4 has been demonstrated to be a ligand for B7-1 (Linsley et al. (1991) J. Exp. Med. 174:561-569) and B7-2 (Freeman et al. (1993) Science 262:909-911). The role of CTLA-4 as an immune attenuator has been Annu. Rev. Immunol hypothesized to be due to it being a competitive antagonist of CD28 costimulation via B7-1/B7-2 binding (see e.g., Thompson and Allison (1997) Immunity 7:445-450). For example, CTLA-4 has been found to have at least a 10-fold higher affinity for B7-1 and B7-2 than CD28 (Linsley et al. (1991) supra; van der Merwe et al. (1997) J. Exp. Med. 185:393-403). The crystal structure of the CTLA-4/B7-1 complex has been described (Stamper et al. (2001) Nature 410:608-611). The interaction of CTLA-4 with B7-1 and B7-2 is reviewed in van der Merwe and Davis (2003). 21:659-684.
Given the known interaction of CTLA-4 with the ligands B7-1 and B7-2, functional anti-CTLA-4 antibodies are typically selected based on their ability to block the binding of CTLA-4 to B7-1 and/or B7-2.